The present invention relates to the use of compounds with a potentiating effect on the activity of antibiotics that are activatable via the EthA enzymatic pathway, for the preparation of a medicament for preventing and/or treating mycobacterial infections such as tuberculosis and leprosy, to pharmaceutical compositions comprising them in combination with an antibiotic that is activatable via the EthA pathway, to compounds having a potentiating effect on the activity of antibiotics that are activatable via the EthA enzymatic pathway, to pharmaceutical compositions comprising them and to their use as medicaments, especially medicaments for preventing and/or treating mycobacterial infections such as tuberculosis and leprosy.
Tuberculosis kills two million people per year worldwide. The AIDS epidemic and the emergence of antibiotic multiresistant strains have contributed toward worsening the impact of this disease, which is considered by the World Health Organization as being responsible for an increasingly dangerous worldwide epidemic, and as being a worldwide health emergency. The WHO estimates that, between 2000 and 2020, close to one billion people will be infected with the tuberculosis bacillus and about 200 million of them will develop the disease, which may lead to the death of 35 million people if no improvements are made in controlling or treating this infection.
An increasing number of Mycobacterium tuberculosis strains are characterized at the present time by multidrug resistance to the first-line antibiotics isoniazid (INH) and rifampicin (RIF). These antibiotics have a high therapeutic index (the therapeutic index of an active principle is the ratio of the therapeutic dose to the toxic dose) and should thus be replaced with second-line antibiotics to which the strains are not resistant, but which have the drawback of having a lower therapeutic index.
Among these second-line antibiotics, ethionamide(2-ethyl thioisonicotinamide: ETH, Trescatyl; CAS number 536-33-4) has been commonly used clinically for more than 35 years mainly in the treatment of pulmonary and extrapulmonary tuberculoses (Mycobacterium tuberculosis), and secondarily for treating infections with atypical mycobacteria (Mycobacterium kansasii) and leprosy (Mycobacterium leprae). ETH is a prodrug that needs to be activated in order for its antibacterial activity to be able to be exerted. The activation of ethionamide is performed by a specific mycobacterial enzyme, the enzyme EthA, which is a flavin monooxygenase of Baeyer-Villiger type. In its normal physiological state, the mycobacterium synthesizes little EthA enzyme, which limits the activation of the prodrug and is reflected by low sensitivity of the bacterium toward this antibiotic. Recently, the mechanism of expression of the gene encoding EthA was elucidated by Baulard et al. (Baulard A. et al., J. Biol. Chem., 2000, 275(36) 28326-28331) and Engohang-Ndong et al. (Engohang-Ndong et al., Mol. Microbiology, 2004, 51(1), 175-188). Expression of the ethA gene is placed under the control of an adjacent gene: the ethR gene. The ethR gene encodes a protein, EthR, which binds to a target DNA sequence upstream of the ethA gene sequence. On binding to the ethA gene promoter, the EthR protein acts as a transcription repressor for this gene. By genetically inactivating the ethR gene, hypersensitivity of the mycobacterium to ethionamide is observed (Baulard et al., 2000, cited previously; Engohang-Ndong et al., 2004, cited previously), due to the non-repression of ethA transcription.
ETH is an antibiotic that is known to greatly inhibit the biosynthesis of mycolic acids, which are essential constituents of the mycobacterial wall. Its presumed target is the enzyme enoyl-AcpM reductase (InhA). Its administration in therapeutically effective doses, generally 10 mg/kg/day (Johnson et al., J. Pharm. Pharmacol., 1967, 19, 1-9) leads, however, to adverse side effects such as liver toxicity, mental impairment (psychoses, anxiety, depression), intestinal disorders, and ocular and auditive impairment (Reynolds J E F et al., 1989, Martindale, the extra pharmacopoeia, 29th ed. London, The Pharmaceutical Press, 562-563). Its use is, however, common in developing countries for the treatment of patients who relapse as a result of infection with strains of M. tuberculosis that are resistant to first-line antibiotics, or for treating patients suffering from lepromatous leprosy, as a replacement for clofazimine.
There is therefore a certain advantage in developing a technical solution for reducing the dose of ETH, and thereby its adverse side effects, while at the same time maintaining or improving its therapeutic efficacy.
With this aim, it has already been envisioned to potentiate the activity of ETH by combining it with a particular compound. Thus, international patent application WO 2005/047 538 describes a process for identifying EthR repressor inhibitors, and also chemical compounds having this effect. Said patent application cites, various compounds in this respect, among which is especially hexadecyl octanoate. The activity of this compound was also studied in the article by Frénois F. et al., Molecular Cell, 2004, 16, 301-307. However, given the length of its carbon chain, hexadecyl octanoate is a compound having very low bioavailability. Moreover, it is not active on live mycobacteria.
In addition, the pathway for activation of the prodrugs by EthA has also been recently illustrated for thiacetazone (Qian L, et al., Chem. Res. Toxicol. 2006, 19, 443-449), and indirectly for isoxyl (DeBarber A E, et al., Proc. Natl. Acad. Sci. USA, 2000, 97, 9677-82). Any compound capable of interfering with the EthA activation pathway should thus allow the action of these prodrugs to be potentiated.
The Inventors thus set themselves the aim of providing compounds that are easier to formulate than hexadecyl octanoate and that can be used in combination with ETH in order to potentiate its activity. This type of medicament might contain, in addition to the compounds forming the subject of the present invention, smaller doses of ETH, while at the same time maintaining efficacy that is at least equivalent to that of a medicament containing only ETH.